16alpha:17alpha-derivatives of 6alpha-methyl steroids



United States Patent 2,630/59 16 Claims. ((11. 26 0-43955) Thisinvention is for improvements in or relating to organic compounds andhas particular reference to new 6- methyl steroids of the pregnaneseries.

It is an object of the present invention to provide new cyclic acetalsand ketals of the 6a-methylpregnane series which are represented byFormula 1 below which are of value on account of their biologicalactivity, and in particular on account of their marked progestationalactivity when administered by the oral route, which property rendersthem valuable in, for example, veterinary practice.

According to the present invention there is provided a process for theprevention of a oat-methyl steroids of the pregnane series having thegeneral formula Ill lo M e ----o R Me (I) where R is hydrogen or analkyl or aryl group and R is an alkyl or aryl group or where R and Rtogether form a ring, which process comprises oxidizing6a-me-thylpregna-4:6-diene-3:ZO-dione having the formula to form 161x217dihydroxy-6a-methylpregn-4-ene3:20-

dione having the formula R.R.C=O where R and R have the same eaning asabove.

3,2723% Patented Sept. 13, wee

ice

Oxidation of 6a-methylpregna-4:16-diene-3z20-dione (II) into the16a:1'7a-dihydroxy-6a-methylpregn-4-ene- 3:20-dione (111) may beachieved with potassium permanganate, for example, in aqueous acetonesolution rendered slightly acid with acetic acid and within thetemperature range 0 to 25 C. The reaction proceeds rapidly under theseconditions, with separation of brown manganese oxides, which areconveniently dissolved at the end of the reaction 'by treating themixture with sulphur dioxide. Thereafter the product (III) may beisolated by, for example, extraction with an organic solvent in which itis soluble and which is immiscible with water, such as ether.

Condensation of the 16a:l7a-dihydroxy-6a-methylpregn-4-ene (HI) withaldehydes or ketones to give the cyclic acetals or ketals (I) may beeiiected by methods established by prior art and in particular bycondensation in the presence of an acidic catalyst. Perchloric acid isthe preferred catalyst. The condensation may be performed atroomtemperature employing a large excess of the aldehyde or ketone whichacts as solvent or alternatively in'the presence of an inert organicsolvent such as benzene.

The invention provides the following new compounds:16a:17a-dihydroxy-6wmethylpregnr-ene 3:20 dione (HI), which is of valueas an intermediate in the preparation or' cyclic acetals and ketalshaving the general Formula I. Got -rnethyl 16a:17a-(2:2-dimethyl-4':5-dioxolane)-pregesterone (I; -R=R=Me), which is of valuable in particularon account of its progestational prop erty when administered by the oralroute, such progestational property being associated with a diureticresponse that may be demonstrated in saline loaded rats. The material isthus of value in the treatment of those conditions in which a diureticeifect is advantageously superimposed upon a progestational effect.

6a-methyl-16a: 17a- 2'-methyl-2-ethyl-4 5'-dioxolane progesterone.

6a-methyl-l 6a: 17a-(2'-methyl-2'-n-propyl-4':S'-dioxolane)-progesterone.

L-I1'16tl1yl16a 17w (2 2-diethyl-4' 5 -dioxolane) -progesterone.

60c methyl 16a:17a-(2'methyl-2'-n-butyl-4':5-dioxo- Jana-progesterone.

6u-methyl-16u:17a-(2':2'-di-n-propyl-4':5-di0xolane)- progesterone.

60 methyl-16a: 17er-(2'-methyl-2'-isobutyl-4 5-dioxolane) -progesterone.

6a-methyl-l6a: 170c-(2' 2-spirocyclo-pentyl-4 5-dioxolane)-progesterone.

6a methyl 16oz:17u-(2:2-spiro-cyclohexyl-4':S-dioxolane)-progesterone.

6OL-1T1GthY1- 1 60a! 17a- 2 2-spiro- (4"-cyclo-methylhexyl) 4'5'-dioxolane -progesterone.

6a-met'hyll 60:: 17oc- (2'-phenyl-4' S '-dioxolane pro gesterone.

604 methyl-16a: 1704-(2'4013'1-4'2 5dioxolane)progesterone.

60: methyl 16a:17a-(2'-rnethyl-2'-phenyl-4:5-dioxolane) -progesterone.

6a methyl 16a: l7a-(2'-methyl-4:5-dioxolane)progesterone (I; R=H, R Me)which is a value on account its progestational properties, and diureticproperties which may be demonstrated in saline loaded rates.

Following is a description by way of example of methods of carrying theinvention into effect:

Example 1 A solution of potassium permanganate (3 g.) in a mixture ofacetone ml.) and water (25 ml.) was added during 20 minutes to a stirredsolution of 6m-methylpregna-4:16-diene-3z20-dione (5.2 g.) in a mixtureof acetone (160 ml.) and acetic acid (1.4 ml.). After treatment withsulphur dioxide, the pale yellow solution was decanted from inorganicsalts, diluted with water, and the product extracted with ether. Theextract was washed with aqueous sodium bicarbonate, water, and thendried. Concentration to 30 ml. gave crystals which were purified fromaqueous ethanol. 16oz:I7a-dihYdIOXY-Gu-In6thYlpregn-4-ene-3z20-dioneseparated in needles, M.P. 223 to 225 C. [a] +82 (c., 0.94 inchloroform), A 240 ma (log 6, 4.19).

A suspension of the foregoing compound (200 mg.) in acetone (15 ml.) wastreated with 1 drop of perchloric acid (72% After 30 minutes, themixture was poured into water and the product collected and purifiedfrom aqueous ethanol. 6e-methyl-16a: 17oc-(2' 2'-dimethyl-4:5-dioxolane)progesterone formed needles, M.P. 167 C., +113 (c., 0.25in chloroform), Amax, 240 mp. (log. 5, 4.17).

Example 2 A suspension of 16a:17a-dihydroxy-6a-methylpregn-4-ene-3:20-dione (300 mg.) (prepared as described in Example 1) inmethylethyl ketone (20 ml.) was treated with 2 drops of perchloric acid(72% After 3 hours, ether (60 ml.) was added, the mixture washed withwater, dried, and the solvents removed. The residue was purified fromaqueous ethanol to give blades of the cyclic ketal represented byFormula I (where R=CH R':C H i.e. 6amethyl-16a:17a-(2'-methyl-2'-ethyl-4:5'-dioxolane)progesterone, M.P. 178to 179 C., +108 (c., 0.41 in chloroform).

Example 3 A suspension of 16a:17oc-dihydroxy-6a-methylpregn-4-ene-3z20-dione (300 mg.) (prepared as described in Example 1) in methyln-propyl ketone (20 ml.) was treated with 2 drops of perchloric acid(72%). Ether (50 ml.) was added after 2 hours, the mixture was washed,dried, and the solvents removed in vacuo. Crystallization of the residuefrom acetone/hexane gave the cyclic ketal represented by Formula I(where R=Me; R'=n-C H i.e. 6a methyl16a:17a-(2'-methyl-2-n-propyl-4':5-dioxolane)progesterone.

Example 4 A suspension of 16a:17a-dihydroxy-6u-methylpregn-4-ene-3z20-dione (200 mg.) (prepared as described in Example 1) in diethylketone (20 ml.) was treated with 2 drops of perchloric acid (72%). After1 hour the mixture was treated with ether (50 ml.), and the productisolated as described in Example 3. It was purified from aqueousmethanol to give the cyclic ketal represented by Formula I (where R=R'=CH i.e. 6a-methyl-16a: l7u- 2' 2-diethyl-4 5 '-dioxolane progesterone.

Example 5 A suspension of 16a:17a-dihydroxy-6a-methylpregn-4-ene-3z20-dione (400 mg.) (prepared as described in Example 1) inhex-an-2-one (20 ml.) was treated with 2 drops of perchloric acid (72%).After 3 hours, ether (60 ml.) was added, the mixture was washed withwater, dried, and the solvents removed in vacuo. The residue waspurified from acetone/hexane to give the cyclic ketal represented byFormula I (where R=CH R=n-C H i.e. 60cmethyl-16a:17a-(2'-methyl-2'-n=butyl-4:5'-dioxolane progesterone.

Example 6 A suspension of 16a:17a-dihydroxy-6u-methylpregn-4-ene-3:20-di0ne (200 mg.) (prepared as described in Example 1) indi-n-propyl ketone (15 ml.) was treated with 1 drop of perchloric acid(72%). After standing overnight, the mixture was diluted with ether (60ml.), washed neutral, dried, and the solvents removed in vacuo.Crystallization of the product from aqueous ethanol gave the cyclicketal represented by Formula I (where i.e. 6a methyl16a:17a-(2':2'-di-n-propyl-4':5'-dioxolane) progesterone.

Example 7 A suspension of 16a:17a-dihydroxy-6a-methylpregn-4-ene-3:20-dione (350 mg.) (prepared as described in Example 1) in methylisobutyl ketone (20 ml.) was treated with 2 drops of perchloric acid(72% After a. reaction period of 4 hours, the product was isolated asdescribed in Example 3, and purified from aqueous ethanol. There wasobtained the cyclic ketal represented by Formula I (where R=CH R'=iso-CH i.e. 6a-methyl-16m17a- (2-methyl-2'-isobutyl-4' 5-dioxoloneprogesterone.

Example 8 A suspension of 16a:17u-dihydroxy-6a-methylpregn-4-ene-3:20-dione (350 mg.) (prepared as described in Example 1 incyclopentanone (15 ml.) was treated with 2 drops of perchloric acid(72%). After standing for 2 hours, ether (60 ml.) was added, the mixturewashed, dried and the solvents removed in vacuo. Crystallization of theproduct from acetone/hexane gave the cyclic ketal represented by FormulaI (where A suspension of 16a:17a-dihydroxy-6a-methylpregn-4-ene-3z20-dione (350 mg.) (prepared as described in Example 1) in4-met-hylcyclohexanone (15 ml.) was treated with 2 drops of perchloricacid (72%). After 4 hours, the mixture was steam-distilled and theproduct isolated with ether. Crystallization gave the cyclic ketalrepre' sented by Formula I (where CH2CH2 RR= 011.011,) CH2CH2 i.e.6a-methyl-16u:17a-(2':2-spiro-(4"-cyclo-methylhex yl)-4':5 -dioxolane)progesterone.

Example 11 A solution of 16a:17a-dihydroxy-6a-methylpregn-4-ene-3:20-dione (400 mg.) (prepared as described in Example 1) inbenzaldehyde (5 ml.) was treated with 1 drop of perchloric acid (72%).After 3 hours, the mixture was submitted to steam-distillation, and theproduct isolated with ether. Crystallization from aqueous ethanol gavethe cyclic ketal represented by Formula I (where R=H; R'=C H plates,M.P. 205 to 207 C., i.e. 6a-methyl- 16a: 17 a-(2'-pheny1-4':5dioxolane)progesterone, [a1 (c., 0.84 in chloroform).

Example 12 A solution of 16a:17a-dihydroxy-6u-methylpregn-4-ene-3:20-di0ne (400 mg.) (prepared as described in Example 1) inp-tolylaldehyde ml.) was treated with 1 drop of perchloric acid (72%).After 3 hours, the mixture was steam-distilled, and the product isolatedwith ether. Purification from acetone/hexane gave the cyclic acetalrepresented by Formula I (where R=H; R'=C H .CH i.e. 6amethyl-16a:l7a-(2f-tolyl-4':5-dioxolane)progesterone.

Example 13 A solution of 16a: l7a-dihydroxy-6 ot-methylpregn4-ene-3:20-dione (400 mg.) (prepared as described in Example 1) in methylphenyl ketone (5 ml.) was treated with 1 drop of perchloric acid (72%).After 5 hours, the mixture was steam-distilled and the product isolatedwith ether. Purification from aqueous methanol gave the cyclic ketalrepresented by Formula I (Where R=CH R'=C H i.e. 6ot-methyl-l6a:170t-(2methy1-2phenyl- 4' 5 '-dioXolane progesterone.

Example 14 A suspension of 16a:l7a-dihydroxy-6tx-methylpregn-4- ene3:20-dione (500 mg.) in paraldehyde (1 ml.) was treated with 2 drops ofperohloric acid (72%). After 2 hours, ether (50 ml.) was added and thesolution washed with aqueous sodium hydrogen carbonate, water, anddried. Removal of the solvents gave a gum which was chromatographed onalumina g.). Elution with benzene-light petroleum (3:2) gave a solidwhich was purified from aqueous methanol. 6a-methyl-l6a:l7a-(2-methyl-4:5-dioxolane)progesterone crystallized in flakes, M.P. 172 to174 C., +123" (c., 0.8 in ohloroform). This compound is represented byFormula I where R=H; R'=Me.

We claim:

1. 6ot-methyl steroids of the pregnane series having the general formulawhere are selected from the group consisting of hydrogen /lower alkyllower alkyl hydrogen hydr0gen lower alkyl lower alkyl phenyl phenyltolyl /CH3CH3 CHI-CH2 CHE-0E2 CH2 and CH. CH3

CHz-CH: CHgCHg GHQ-CH2 2. 16ot217a dihydroxy 6a methylpregn-4-ene-3220dione.

3. 6oz methyl l6uzl7a (2':2'-dimethyl-4:5'-dioxolane) -progesterone.

4. 6ot-methyl-l6a: l7a-(2-methyl-2-ethyl 4':5'-dioxolane) -progesterone.

5. 60a methyl-16a:17w(2'-methyl-2'-n-propyl 4:5'- dioxolane)-progesterone.

6. 6a methyl 16oc217oc (2':2'-diethyl-4:5-dioxolane) -progesterone.

7. 60a methyl 16a:17a-(2'-methyl-2-n-butyl-4:5'- dioxolane)-progesterone.

8. 6a-methyl 160121704 (2:2-di-n-propyl-4'-5-dioxolane) -progesterone.

9. 60a methyl 16a:17a-(2-methyl-2'-isobutyl-4:5- dioxolane)-pr0gester0ne.

10. 6oz methyl 1612:1170: (2':2'-spiro-cyclo-pentyl- 4' 5 '-dioxolane-progesterone.

11. 60c methyl-16a:17a-(2:2'-spiro-cycloheXyl-4:5- dioxolane-progesterone.

12. 6a methyl-16a:17a-(2:2'-spiro-(4"-cyclo-methy1- hexyl) -4'5-diox0lane) -progesterone.

13. 60c methyl 161x:l7a-(2-phenyl-4:5'-dioxolane)- progesterone.

14. 60c methyl 16a: 17a (2'-tolyl-4':5'-dioxolane)- progesterone.

15. 6a methyl 16a117oc (2'-methyl-2'-phenyl-4':5'- dioxolane-progesterone.

16. 6a methyl 16a: l7a-(2'-methyl-4':5'-dioXolane)- progesterone.

References Cited by the Examiner UNITED STATES PATENTS 2,727,909 12/1955Colton 260-3974 2,864,838 12/1958 Lincoln et a1 260---397.45

OTHER REFERENCES Burn et al.: J. Chem. Soc., London (September 1957),pp. 4092-4098.

Cooley et al.: J. Chem. Soc., London (December 1955), pp. 4373-4377.

Fried et al.: J. Am. Chem. Soc., vol. (May 5, 1958), pages 2338 and2339.

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, MAYER LIEBMAN,

Examiners.

T. I. MORGAN, M. L. WILLIAMS,

Assistant Examiners.

1. 6A-METHYL STERIODS OF THE PREGNANE SERIES HAVING THE GENERAL FORMULA